Benzyloxy anilide derivatives useful as potassium channel modulators

ABSTRACT

The present invention relates to benzyloxyanilide derivatives having the following structural formula: 
                         
The compounds of the present invention are useful for the treatment and prevention of diseases and disorders which are affected by activation or modulation of potassium ion channels. One such condition is seizure disorders.

This application is a divisional application of Ser. No. 12/491,055,filed on Jun. 24, 2009, now U.S. Pat. No. 8,188,314, which claims thebenefit of priority of U.S. provisional application Ser. No. 61/075,307,filed Jun. 24, 2008, the entire contents of each of the applications areincorporated herein by reference.

FIELD OF THE INVENTION

This invention provides benzyloxy anilide derivatives which activate orotherwise modulate voltage-gated potassium channels. The compounds areuseful for the treatment and prevention of diseases and disorders whichare affected by modulation of potassium ion channels. One such conditionis seizure disorders.

BACKGROUND OF THE INVENTION

Epilepsy is a well-known neurological disease, found in about 3% of thepopulation. Approximately 30% of patients with epilepsy do not respondto currently available therapies. Such unfortunate patients—who numberhundreds of thousands of people world-wide—must contend with bothuncontrolled seizures and the resulting narrowing of their options insuch crucial areas of life as health insurance, employment, and driving.

Retigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid,ethyl ester) (U.S. Pat. No. 5,384,330) has been found to be an effectivetreatment of seizure disorders and has also been found useful intreating pain. Retigabine has been found to be particularly potent inmodels for the drug-refractory types of epilepsy. Bialer, M. et al.,Epilepsy Research 1999, 34, 1-41; Blackburn-Munro and Jensen, Eur. J.Pharmacol. 2003, 460, 109-116; Wickenden, A. D. et al., Expert Opin.Ther. Patents, 2004, 14(4).

“Benign familial neonatal convulsions,” an inherited form of epilepsy,has been associated with mutations in the KCNQ2/3 channels. Biervert, C.et al., Science 1998, 27, 403-06; Singh, N. A., et al., Nat. Genet.1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55;Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequentinvestigations have established that one important site of action ofretigabine is the KCNQ2/3 channel. Wickenden, A. D. et al., Mol.Pharmacol. 2000, 58, 591-600; Main, M. J. et al., Mol. Pharmcol. 2000,58, 253-62. Retigabine has been shown to increase the conductance of thechannels at the resting membrane potential, with a possible mechanisminvolving binding of the activation gate of the KCNQ 2/3 channel.Wuttke, T. V., et al., Mol. Pharmacol. 2005. Additionally, retigabinehas been shown to increase neuronal M currents and to increase thechannel open probability of KCNQ 2/3 channels. Delmas, P. and Brown, D.A. Nat. Revs Neurosci., vol. 6, 2005, 850-62; Tatulian, L. and Brown, D.A., J. Physiol., (2003) 549, 57-63.

The seizure type that has been most resistant to therapy is theso-called “complex partial seizure.” Retigabine is active in severalseizure models, including, as indicated above, models fordrug-refractory epilepsy. Because of retigabine's broad spectrum ofactivity and its unusual molecular mechanism, there is hope thatretigabine will be effective in management of several seizure types,including the complex partial seizure, which have been resistant totreatment. Porter, R. J., Nohria, V., and Rundfeldt, C.,Neurotherapeutics, 2007, vol. 4, 149-154.

The recognition of retigabine as a potassium channel opener has inspireda search among compounds with structural features in common withretigabine for other compounds which can affect the opening of, orotherwise modulate, potassium ion channels.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I

wherein R₁ and R₂, are, independently, H, CN, halogen, CH₂CN, OH, NO₂,CH₂F, CHF₂, CF₃, CF₂CF₃, C₁-C₆ alkyl, C(═O)C₁-C₆alkyl; NH₂, NH—C₁-C₆alkyl; N(C₁-C₆alkyl)-C₁-C₆ alkyl, NHC(═O)C₁-C₆ alkyl, C(═O)N(CH₃)₂,C(═O)N(Et)₂, C(═O)NH₂, C(═O)NH—C₁-C₆ alkyl, SO₂NH₂, NHSO₂—C₁-C₆ alkyl;C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl, SC₁-C₆ alkyl, C₃-C₆cycloalkyl, (CH₂)_(m)C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl,(CH₂)_(m)C₃-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar,(CH₂)_(m)thienyl, (CH₂)_(m)furyl, (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl,(CH₂)_(m)oxazolyl, (CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl,(CH₂)_(m)isothiazolyl, (CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl,(CH₂)_(m)pyridyl, or (CH₂)_(m)pyrimidyl, which cycloalkyl and saidcycloalkenyl groups optionally contain one or two heteroatoms selectedindependently from O, N, and S, and which are optionally substituted asdescribed below; wherein m is zero, 1, or 2, Ar is a 5- to 10-membermono- or bicyclic aromatic group, optionally containing 1-4 ringheteroatoms selected independently from N, O, and S; or R₁ and R₂,together with the ring carbon atoms to which they are attached, form a5- or 6-member fused ring, which ring may be saturated, unsaturated, oraromatic, which optionally contains one or two heteroatoms selectedindependently from O, N, and S, and which is optionally substituted asdescribed below; R₃ and R₄ are, independently, H, CN, halogen, CF₃,OCF₃, OC₁-C₃ alkyl, or C₁-C₆ alkyl; X═O or S; Y is O or S; q=1 or zero;R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₅)_(w)CH₂C₃-C₆cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar,(CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, wherein w=zero, 1, 2,or 3, Ar is a 5- to 10-member mono- or bicyclic aromatic group,optionally containing 1-4 ring heteroatoms selected independently fromN, O, and S; R₆ is H or C₁-C₃ alkyl; wherein all cycloalkyl andcycloalkenyl groups optionally contain one or two ring heteroatomsselected independently from N, O, and S; wherein all alkyl, cycloalkyl,alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl,aryl, and heteroaryl groups in R₁, R₂, R₃, R₄, R₅, R₆, and Ar areoptionally substituted with one or two substituents selectedindependently from C₁-C₃ alkyl, OCF₃, halogen, CN, OH, OMe, OEt, CN,CH₂F, and trifluoromethyl; and wherein, additionally, all cycloalkyl andheterocycloalkyl groups are optionally substituted with a carbonylgroup, and halogen designates Cl, F, Br or I and the terms alkyl refersto branch or unbranched alkyl groups and pharmaceutically acceptablesalts, solvates, and esters thereof. Such compounds are potassiumchannel activators or modulators.

Essentially all combinations of the several variables in formula I areembraced by this invention.

In another embodiment, this invention provides a composition comprisinga pharmaceutically acceptable carrier or diluent and at least one of thefollowing: a pharmaceutically effective amount of a compound of formulaI, a pharmaceutically acceptable salt of a compound of formula I, apharmaceutically acceptable solvate of a compound of formula I, and apharmaceutically acceptable ester of a compound of formula I.

In yet another embodiment, this invention provides a pediatricpharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent, a syrup for pediatric use, and at least one of thefollowing: a pharmaceutically effective amount of a compound of formulaI, a pharmaceutically acceptable salt of a compound of formula I, apharmaceutically acceptable ester of a compound of formula I, and apharmaceutically acceptable solvate of a compound of formula I.

In yet another embodiment, this invention provides a chewable tablet,suitable for pediatric pharmaceutical use, comprising a pharmaceuticallyacceptable carrier or diluent, and at least one of the following: apharmaceutically effective amount of a compound of formula I, apharmaceutically acceptable salt of a compound of formula I, apharmaceutically acceptable solvate of a compound of formula I, and apharmaceutically acceptable ester of a compound of formula I.

In yet another embodiment, this invention provides a method ofpreventing or treating a disease or disorder which is affected byactivation voltage-gated potassium channels, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of formula IA or a salt or ester or solvate thereof.

This invention includes all tautomers and salts of compounds of thisinvention. This invention also includes all compounds of this inventionwherein one or more atoms are replaced by a radioactive isotope thereof.

This invention provides compounds of formula I above wherein the groupNH—C(═X)—(Y)_(q)—R₅ is each of the following: NHC(═O)R₅, NHC(═O)OR₅,NHC(═S)R₅, NHC(═S)SR₅, NHC(═S)OR₅, and NHC(═O)SR₅.

Thus, in one embodiment, this invention provides a compound of formulaI, wherein NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)R₅.

In another embodiment, this invention provides a compound of formula I,wherein NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)R₅.

In another embodiment, this invention provides a compound of formula I,wherein NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)SR₅.

In another embodiment, this invention provides a compound of formula I,wherein NH—C(═X)—(Y)_(q)—R₅ is each NHC(═O)OR₅.

In another embodiment, this invention provides a compound of formula I,wherein NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)OR₅.

In another embodiment, this invention provides a compound of formula I,wherein NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)SR₅.

In another generic embodiment, this invention provides a compound offormula I, wherein q is zero and R₅ is C₁-C₆alkyl, or (CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula Iwherein R, is located as shown below:

In another embodiment, R₁ is located as shown below:

In another embodiment, R₁ is located as shown below

In another embodiment, this invention provides a compound of formula I,wherein R₂ is H.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is halogen.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is Cl or F.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is trifluoromethyl.

In another embodiment, this invention provides a compound of formula I,wherein R₃ and R₄ are, independently, H, Cl, methyl, ethyl,trifluoromethyl, or methoxy.

In another embodiment, this invention provides a compound of formula I,wherein q is zero and R₃ and R₄ are Cl, ethyl, methoxy, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein q is zero and R₃ and R₄ are both methyl.

In another embodiment, this invention provides a compound of formula I,wherein R₃ and R₄ are, independently, H, Cl, ethyl, methoxy, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein R₃ and R₄ are, independently, H, Cl, ethyl, methoxy, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein R₃ and R₄ are, independently, H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein q is zero, and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein q is 1; Y is O; and R₅ is C₁-C₆ alkyl, or(CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein q is 1; Y is S; and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is H and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is H and R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is H and R₅ is (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formula I,wherein R₂ is H and R₅ is CR₆═CH—C₃-C₆ cycloalkyl or CH═CR₆—C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₃ and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is Cl or F; and R₃ and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is Cl or F; R₃ and R₄ are H, Cl, ethyl, or methyl; and R₅ isC₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is phenyl, optionally substituted.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is phenyl, optionally substituted, and R₅ is C₁-C₆ alkyl, or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is NH—C₁-C₆ alkyl, N(C₁-C₆ alkyl)-C₁-C₆ alkyl, C(═O)NH—C₁-C₆alkyl, NH—C(═O)C₁-C₆ alkyl; O—C₁-C₆ alkyl, C(═O)—C₁-C₆ alkyl,C(═O)—OC₁-C₆ alkyl, or OC(═O)C₁-C₆ alkyl; and R₅ is C₁-C₆ alkyl, or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is NH—C₁-C₆ alkyl, N(C₁-C₆ alkyl)-C₁-C₆ alkyl, C(═O)NH—C₁-C₆alkyl, or NH—C(═O)C₁-C₆ alkyl.

In yet another embodiment, this invention provides a compound of formulaI, wherein R₁ is C(═O)OC₁-C₆alkyl, OC(═O)C₁-C₆alkyl, or OC₁-C₆ alkyl.

In another specific embodiment, this invention provides a compound offormula I, wherein R₁ is H, methyl, methoxy, or halogen, and R₂ ismethyl or ethyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is H, methyl, methoxy, or halogen, and R₂ is phenyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is H, methyl, methoxy, or halogen, and R₂ is F.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is methoxy, methoxymethyl, ethoxymethyl, or methoxyethyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is methoxy, methoxymethyl, ethoxymethyl, or methoxyethyl; R₂is H, methyl, or halogen; and R₃ is methyl or Cl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is phenyl, optionally substituted, and R₂ is H, methyl,methoxy, or halogen.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is CF₃ or C₁-C₃ alkyl, and R₂ is H, methyl, methoxy, orhalogen.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is methoxy, and R₂ is H, methyl, methoxy, or halogen.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is 2-dimethylamino ethyl, and R₂ is H, methyl, methoxy, orhalogen.

In another embodiment, this invention provides a compound of formula I,wherein q is zero, R₂ is H, methyl, methoxy, or halogen, R₁ is phenyl,optionally substituted; and R₃ and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein q is zero, R₂ is H, methyl, methoxy, or halogen; R₁ is CF₃ orC₁-C₃ alkyl; and R₃ and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein q is zero, R₂ is H, methyl, methoxy, or halogen; R1 is F; and R₃and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, this invention provides a compound of formula I,wherein q is zero; R₁ is Br; R₂ is H, methyl, methoxy, or halogen; andR₃ and R₄ are H, Cl, ethyl, or methyl.

In another embodiment, the invention provides a compound of formula IA-1below.

wherein R₁ is selected from the group consisting of H, halogen, CN,CH₂CN, CHF₂, CF₃, C₁-C₆ alkyl, OCH₃, (C═O)OCH₃, O(C═O)CH₃, OCF₃,(CH₂)_(m)C₃-C₆ cycloalkyl, phenyl, and pyridyl; R₂ is selected from thegroup consisting of H, F, OCH₃, CH₃, and CF₃; R₃ and R₄, areindependently, selected from the group consisting of H, F, Cl, CF₃,OCF₃, OC₁-C₃ alkyl, and C₁-C₃ alkyl; and R₅ is selected from the groupconsisting of C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)wCH₂C₃-C₆cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar,(CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, and (CHR₆)_(w)CH₂Ar, wherein w=0-3, Ar isselected from the group consisting of phenyl, furyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, and pyridyl; and R₆ is C₁-C₃ alkyl; wherein allalkyl, cycloalkyl, aryl, and heteroaryl groups in R₁, R₂, R₃, R₄, R₅,and R₆, and Ar are optionally substituted with one or two substituentsselected independently from C₁-C₃ alkyl, halogen, OCH₃, OCH₂CH₃, CN, andCF₃.

In another embodiment, this invention provides a compound of formulaIA-2 below.

wherein R₁ is selected from the group consisting of H, halogen, CN,CH₂CN, CHF₂, CF₃, C₁-C₆ alkyl, OCH₃, (C═O)OCH₃, O(C═O)CH₃, OCF₃,(CH₂)_(m)C₃-C₆ cycloalkyl, phenyl, and pyridyl; R₂ is selected from thegroup consisting of H, F, OCH₃, CH₃, and CF₃; R₃ and R₄, areindependently, selected from the group consisting of H, F, Cl, CF₃,OCF₃, OC₁-C₃ alkyl, and C₁-C₃ alkyl; and R₅ is selected from the groupconsisting of C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)wCH₂C₃-C₆cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar,(CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, and (CHR₆)_(w)CH₂Ar, wherein w=0-3, Ar isselected from the group consisting of phenyl, furyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, and pyridyl; and R₆ is C₁-C₃ alkyl; wherein allalkyl, cycloalkyl, aryl, and heteroaryl groups in R₁, R₂, R₃, R₄, R₅,and R₆, and Ar are optionally substituted with one or two substituentsselected independently from C₁-C₃ alkyl, halogen, OCH₃, OCH₂CH₃, CN, andCF₃.

In still another embodiment, this invention provides a compound offormula IA-3 below.

In yet another embodiment, this invention provides a compound of formulaIB-1 below.

In another specific embodiment, this invention provides a compound offormula IB-2 below.

In another specific embodiment, this invention provides a compound offormula IB-3 below.

In formulas IA-3, IB-1, IB-2 and IB-3, R₁, R₂, R₃, R₄ and R₅ are definedas in formula I.

In another more specific embodiment, this invention provides a compoundof formula IA-1, formula IA-2, or formula IA-3, wherein R₂ is H, alkyl,or halogen; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another specific embodiment, this invention provides a compound offormula IA-1, formula IA-2, or formula IA-3, wherein R₁ is(CH₂)_(m)C₃-C₆ cycloalkyl; R₂ is H, alkyl, or halogen; and R₅ is C₁-C₆alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another specific embodiment, this invention provides a compound offormula IA-1, formula IA-2, or formula IA-3, wherein R₁ is methoxy,methoxymethyl, or methoxyethyl; R₂ is H, alkyl, or halogen; and R₅ isC₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In yet another specific embodiment, this invention provides a compoundof formula IA-1, wherein R₅ is C₁-C₆ alkyl, (CHR₅)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In yet another specific embodiment, this invention provides a compoundof formula IA-2, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In yet another specific embodiment, this invention provides a compoundof formula IA-1, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In yet another specific embodiment, this invention provides a compoundof formula IA-2, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In yet another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In yet another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In yet another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In yet another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is H; R₃ is methyl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In yet another embodiment, this invention provides a compound of formulaIA-2, wherein R₂ is H; R₃ is methyl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In yet another embodiment, this invention provides a compound of formulaIA-3, wherein R₂ is H; R₃ is methyl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl,methoxyethyl, or trifluoromethyl; R₃ is methyl; and R₅ is C₄-C₆ alkyl,(CHR₆)_(w)CH₂C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl,methoxyethyl, or trifluoromethyl; R₃ is methyl; and R₅ is C₄-C₆ alkyl,(CHR₆)_(w)CH₂C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy,methoxymethyl, ethoxymethyl, methoxyethyl, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy,methoxymethyl, ethoxymethyl, methoxyethyl, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl,methoxyethyl, or trifluoromethyl; R₂ is H, methyl, or F; R₃ is methyl;R₄ is methyl or Cl; and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl,methoxyethyl, or trifluoromethyl; R₂ is H, methyl, or F; R₃ is methyl;R₄ is methyl or Cl; and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl,methoxyethyl, or trifluoromethyl; R₂ is H, methyl, or F; R₃ is methyl;R₄ is methyl or Cl; and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is (CH₂)_(m)C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, or(CH₂)_(m)C₃-C₆ cycloalkenyl; and R₃ is methyl or Cl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is (CH₂)_(m)C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, or(CH₂)_(m)C₃-C₆ cycloalkenyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is methoxy, methoxymethyl, ethoxymethyl; ormethoxyethyl; R₂ is H or F; R₃ is methyl; R₄ is methyl or Cl; and R₅ is(CHR₆)_(w)C₅-C₆ cycloalkenyl or (CHR₆)_(w)Ar.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is phenyl, optionally substituted.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is methyl, halomethyl, ethyl, or haloethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is C₁-C₄ alkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is methyl or ethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is fluoro, R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₂ is 4-fluoro, R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R, is (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl, (CH₂)_(m)furyl, (CH₂)_(m) thienyl, (CH₂)_(m)oxazolyl, (CH₂)_(m)isoxazolyl,(CH₂)_(m)thiazolyl, (CH₂)_(m)isothiazolyl, (CH₂)_(m)phenyl,(CH₂)_(m)pyrrolyl, (CH₂)_(m)pyridyl, or (CH₂)_(m)pyrimidyl; and R₂ is H.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl,(CH₂)_(m)furyl, (CH₂)_(m)thienyl, (CH₂)_(m)oxazolyl,(CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl, (CH₂)_(m)isothiazolyl,(CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl, (CH₂)_(m)pyridyl, or(CH₂)_(m)pyrimidyl; R₂ is H and R₅ is pyridyl or phenyl, optionallysubstituted.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₂ is CF₃ or C₁-C₃ alkyl; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₃ and R₄ are methyl or trifluoromethyl; R₅ is C₄-C₆alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; andR₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₂ is methoxy or ethoxy; and R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₂ is phenyl, optionally substituted; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl,(CH₂)_(m)furyl, (CH₂)_(m)thienyl, (CH₂)_(m)oxazolyl,(CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl, (CH₂)_(m)isothiazolyl,(CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl, (CH₂)_(m)pyridyl, or(CH₂)_(m)pyrimidyl; R₂ is H; and R₅ is pyridyl or phenyl, optionallysubstituted.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is CF₃ or C₁-C₃ alkyl; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are methyl or trifluoromethyl; R₅ is C₄-C₆alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; andR₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is methoxy or ethoxy; and R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is phenyl, optionally substituted; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is 4-phenyl, optionally substituted; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is CF₃ or C₁-C₃ alkyl; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is 4-methyl or 4-ethyl; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is methoxy or ethoxy, R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl; R₅ isC₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₂ is H, F, or methyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is H.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is halogen.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is F.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is methyl or ethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is methyl or ethyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is halogen; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is H; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is 1-phenyl, optionally substituted.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is 4-phenyl, optionally substituted.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R′ is CF₃ or C₁-C₃ alkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R′ is H; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R′ is F; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R′ is 1-phenyl, optionally substituted; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R′ is 4-phenyl, optionally substituted; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₂ is CF₃ or C₁-C₃ alkyl; R₅ is C₄-C₆ alkyl,(CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ isH, F, Cl, Br, methoxy, or trifluoromethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ and R₂, are, independently, H, CN, F, Cl, Br, CH₂CN,OCH₃, CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃; CH₂F, CHF₂, CF₃, CF₂CF₃, or C₁-C₆alkyl and R₅ is C₁-C₆ alkyl or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, whereinw=0, 1, or 2.

In another embodiment, this invention provides a compound of formulaIA-1, R₁ is H, CN, F, Cl, Br, CH₂CN, OCH₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, CH₂F, CHF₂, CF₃, CF₂CF₃, or C₁-C₆ alkyl; R₂ is H, F, Cl, ormethyl; R₃ is methyl or chloro; and R₅ is C₁-C₆ alkyl orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, wherein R₆ is H or methyl and w=1 or 2.

In another embodiment, this invention provides a compound of formula IA,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar₁.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formula I,wherein R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formula I,wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIB-1, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIB-2, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formulaIB-3, wherein R₅ is haloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₅ is methoxy alkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₅ is cyano alkyl.

In another embodiment, the invention provides a compound of formula I,wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-1, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-2, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-3, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-1, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-2, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-3, wherein R₅ is CH₂-cycloalkyl or CH₂CH₂-cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-1, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-2, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-3, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-1, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-2, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIB-3, wherein R₅ is CH₂—C₅-C₆ cycloalkyl or CH₂CH₂—C₅-C₆ cycloalkyl.

In another embodiment, the invention provides a compound of formulaIA-1, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, the invention provides a compound of formulaIA-2, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, the invention provides a compound of formulaIA-3, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, the invention provides a compound of formulaIB-1, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, the invention provides a compound of formulaIB-2, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, the invention provides a compound of formulaIB-3, wherein R₅ is C₅-C₆ alkyl or CH₂C₅-C₆ alkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are chloro, methoxy, or methyl and R₅ isCH₂-cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are chloro, methoxy, or methyl and R₅ ishaloalkyl, hydroxyalkyl, or methoxyalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are methyl and R₅ is C₅-C₆ alkyl or methoxyalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₃ and R₄ are methyl and R₅ is C₅-C₆ alkyl or chloroalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₃ and R₄ are trifluoromethyl and R₅ is methoxyalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is 2-(2-halocyclopentyl)ethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is 2-(2-furyl)ethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is2-(2-tetrahydrofuryl)ethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is 2-phenyl ethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is 3-phenyl propyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are both methyl and R₅ is 2-phenyl propyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)al₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; and R₁is halogen.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R₂ is Hor halogen; and R₁ is halogen.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R₂ is Hor halogen; and R₁ is halogen.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R₂ is Hor halogen; and R₁ is halogen.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is C₁-C₆ alkyl or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R₂ ishydrogen; and R₁ is halogen.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R₂ ishydrogen; and R₁ is halogen.

In another embodiment, this invention provides a compound of formula I,wherein R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formula IA,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar₁.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is haloalkyl; R₂ is H or F; R₃ and R₄ are Cl, methoxy,or methyl; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₅)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula IA,wherein R₁ is C₁-C₃ alkyl, halogen, or haloalkyl; R₂ is H or F; R₃ andR₄ are H, methyl, or Cl; and R₅ is CH₂CR₆—C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₄-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is C₁-C₃ alkyl, halogen, or haloalkyl; R₂ is H or F; R₃and R₄ are H, methyl, or Cl; and R₅ is CH₂CR₆—C₃-C₆ cycloalkyl,CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is C₁-C₃ alkyl, halogen, or haloalkyl; R₂ is H or F; R₃and R₄ are H, methyl, or Cl; and R₅ is CH₂CR₆—C₃-C₆ cycloalkyl,CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₄-C₆ alkyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R, is C₁-C₃ alkyl, halogen, or haloalkyl; R₂ is H or F; R₃and R₄ are H, methyl, or Cl; and R₅ is CH₂CR₆—C₃-C₆ cycloalkyl, or C₂-C₆alkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is C₁-C₃ alkyl, halogen, or haloalkyl; R₂ is H or F; R₃and R₄ are H, methyl, or Cl; and R₅ is CH₂CR₆—C₃-C₆ cycloalkyl,(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is halogen or haloalkyl; R₂ is H or F; and R₅ isCR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is halogen or haloalkyl; R₂ is H or F; and R₅ isCR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is halogen or haloalkyl; R₂ is H or F; R₃ and R₄ areCl, methoxy, or methyl; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is halogen or haloalkyl; R₂ is H or F; and R₅ isCR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is methyl, fluoro, or fluoroalkyl; R₂ is H or F; and R₅is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is Cl, F, or CF₃; R₂ is H or F; R′ is H or CH₃; and R₅is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is Cl, F, or CF₃; R₂ is H or F; R′ is H or CH₃; and R₅is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; and R₅ is CR₆═CH—C₃-C₆cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; and wherein R₁ and R₂, onadjacent carbons, form a six-membered ring.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; wherein R₅ is C₂-C₆ alkyl,CH₂—C₅-C₆ cycloalkyl, CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, or C₂-C₆ alkenyl; and wherein R₁ and R₂, are onadjacent carbons, and are both other than H.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; wherein R₅ is C₂-C₆ alkyl,CH₂—C₅-C₆ cycloalkyl, CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, or C₂-C₆ alkenyl; and wherein R₁ and R₂, onadjacent carbons, are both halogen.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₃ and R₄ are H, methyl, or Cl; wherein R₅ is C₂-C₆ alkyl,CH₂—C₅-C₆ cycloalkyl, CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, or C₂-C₆ alkenyl; and wherein R₁ and R₂, onadjacent carbons, are both fluorine.

In an embodiment, this invention provides a compound of formula IA-1,wherein R′ is F, methyl, or H; R₃ and R₄ are H, methyl, or Cl; and R₅ isC₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is F, methyl, or H; R₅ is CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R′ is halogen and R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar₁.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ and R₂ are on adjacent carbon atoms and are both otherthan H.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₁ and R₂, on adjacent carbon atoms are, independentlytrifluoromethyl or halogen; and wherein R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is halogen and R₂ is H, or R₁ and R₂, on adjacentcarbon atoms are, independently trifluoromethyl or halogen; and whereinR₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar₁.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is halogen or trifluoromethyl and R₂ is H, or R₁ andR₂, on adjacent carbon atoms are, independently trifluoromethyl orhalogen; and wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formula IA,wherein X is S, q=1, Y is O, and R₅ is C₁-C₆alkyl, (CHR6)_(w)C₃-C₆cycloalkyl, (CHR6)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR6)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula IA,wherein X is S, q=1, Y is O, and R₅ is CR6=CH—C₃-C₆ cycloalkyl,CH═CR6-C₃-C₆ cycloalkyl, (CHR6)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR6)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formula IA,wherein X is S, q=1, Y is O, and R₅ is Ar, (CHR6)_(w)Ar,CH₂(CHR6)_(w)Ar, or (CHR6)_(w)CH₂Ar.

In another embodiment, this invention provides a compound of formula IA,wherein X is S, q=zero, and R₅ is C₁-C₆ alkyl, (CHR6)_(w)C₃-C₆cycloalkyl, (CHR6)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR6)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula IA,wherein X is S, q=zero, and R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another embodiment, this invention provides a compound of formulaIA-2 wherein R₅ is C₁-C₆alkyl or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₅ is C₁-C₆ alkyl or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is halogen or trifluoromethyl and R₂ is H or R₁ and R₂,on adjacent carbon atoms, are, independently, halogen ortrifluoromethyl; and R₅ is C₁-C₆ alkyl or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is halogen or trifluoromethyl and R₂ is H or R₁ and R₂,on adjacent carbon atoms, are, independently, halogen ortrifluoromethyl; and R₅ is C₁-C₆ alkyl or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ and R₂ are, independently, methyl, methoxy,trifluoromethyl, F, Cl, or H; and R₅ is C₁-C₆alkyl or (CHR₆)_(w)C₃-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ and R₂ are, independently, methyl, methoxy,trifluoromethyl, F, Cl, or H; R′ is H; and R₅ is C₁-C₆ alkyl or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2 or IA-3, wherein R₁ is halogen, C₁-C₆ alkyl, mono-haloC₁-C₆ alkyl, CN, di-halo C₁-C₆ alkyl, CF₃, CN, or O—C₁-C₆ alkyl; R′ ismethyl or ethyl; and R₅ is C₅-C₆ alkyl or CH₂—C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2 or IA-3, wherein R₁ is H, halogen, cyano, CF₃, or methoxy,R₂ is H, F, or methyl, R′ is H, halogen, methyl, ethyl, or methoxy, andR₅ is C₅-C₆ alkyl or CH₂—C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is F, Cl, or CF₃; R₂ is H; and R′ is halogen, methyl, ethyl,or methoxy; R₃ and R₄ are H, methyl, or Cl; and R₅ is C₅-C₆ alkyl orCH₂—C₃-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is halogen or CF₃; R₂ is H, F, or methyl, R′ is phenyl; R₃and R₄ are H, methyl, or Cl; and R₅ is C₅-C₆alkyl or CH₂—C₅-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is halogen or CF₃; R₂ is H, F, or methyl, R′ is halophenyl;R₃ and R₄ are 1-1, methyl, or Cl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is NH₂, NH—C₁-C₆ alkyl; N(C₁-C₆ alkyl)-C₁-C₆ alkyl,NHC(═O)C₁-C₆ alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, C(═O)NH—C₁-C₆alkyl, SO₂NH₂, NHSO₂—C₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formula Iwherein R₁ is NH₂, NH—C₁-C₆ alkyl; or N(C₁-C₆ alkyl)-C₁-C₆ alkyl; and R₂is H or halogen.

In another embodiment, this invention provides a compound of formula Iwherein R₁ is NHC(═O)C₁-C₆alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, orC(═O)NH—C₁-C₆alkyl.

In another embodiment, this invention provides a compound of formula 1wherein R₁ is NHC(═O)C₁-C₆alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, orC(═O)NH—C₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formula 1wherein R₁ is SO₂NH₂ or NHSO₂—C₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formulaIA-2 wherein R₁ is SO₂NH₂ or NHSO₂—C₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆alkyl, OC₁-C₆alkyl, orSC₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is (CH₂)_(w)C₃-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is CH₂OCH₃, CH₂OCH₂CH₃, OC₁-C₆alkyl, or SC₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆alkyl, OC₁-C₆ alkyl,or SC₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is CH₂OCH₃, CH₂OCH₂CH₃, OC₁-C₆alkyl, or SC₁-C₆ alkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl,or SC₁-C₆ alkyl; R₂ is H, F, or methyl, R′ is halogen or methyl; and R₅is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is NH₂, NH—C₁-C₆ alkyl; or N(C₁-C₆ alkyl)-C₁-C₆ alkyl;R₂ is H, F, or methyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl orCH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is NHC(═O)C₁-C₆ alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂,C(═O)NH₂, C(═O)NH—C₁-C₆ alkyl, SO₂NH₂, or NHSO₂—C₁-C₆ alkyl; R₂ is H, F,or methyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is C₂-C₆ alkynyl, optionally substituted.

In another embodiment, this invention provides a compound of formula I,wherein R, and R₂ form a fused, nitrogen-containing ring.

In another embodiment, this invention provides a compound of formula I,wherein R₁ and R₂ form a fused, oxygen-containing ring.

In another embodiment, this invention provides a compound of formula I,wherein R₁ and R₂ form a fused thiazolo or isothiazolo group.

In another embodiment, this invention provides a compound of formula I,wherein R₁ and R₂ form a fused cyclopentane, optionally substituted.

In another embodiment, this invention provides a compound of formula I,wherein R₁ and R₂ form a fused cyclohexane, optionally substituted.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused, nitrogen-containing ring.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused, oxygen-containing ring.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused thiazolo or isothiazologroup.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused cyclopentane, optionallysubstituted.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused cyclohexane, optionallysubstituted.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused, nitrogen-containing ring;and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused, oxygen-containing ring;and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused thiazolo or isothiazologroup; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused cyclopentane, optionallysubstituted; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ and R₂ form a fused cyclohexane, optionallysubstituted; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is halogen; R₂ is H, F, or methyl, R′ is halogen ormethyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is halogen; R₂ is H, F, or methyl, R′ is2-(dimethylamino)ethyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is halogen; R₂ is H, halogen, or methyl, R′ is H; andR₅ is C₅-C₆alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is halogen; R₂ is H or methyl, R′ is halogen or methyl;and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is Br, Cl, F or methyl; R₂ is H or F and R₅ is t-butylor cyclopentylmethyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is trifluoromethyl; R₂ is H or methyl, R′ is halogen ormethyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ wherein R₁ is trifluoromethyl; R₂ is H or methyl, R′ ishalogen or methyl; and R₅ is C₅-C₆alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ wherein R₁ is trifluoromethyl; R₂ is H or methyl, R′ ishalogen or methyl; and R₅ is C₅-C₆alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-1 or IA-2, wherein R₁ wherein R₁ is trifluoromethyl; R₂ is H ormethyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is trifluoromethyl; R₂ is F; R′ is halogen or methyl;and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is phenyl, pyridyl,pyrrolyl, imidazolyl, oxazolyl, or thiazolyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is F.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is Cl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is Br.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is F.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is Cl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is Br.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is F and R₂ is H, OCH₃, or F.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is F; R₃ and R₄ are both methyl; and R′ is H.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is CF₃; R₃ and R₄ are both methyl; and R′ is H.

In another embodiment, this invention provides a compound of formula I,wherein R₁ and R₂ are both F.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is mono-, di-, or tri-halomethyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is CH₂F, CHF₂, or CF₃.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is CH₂Cl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ is CH₂Br.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ and R₂ are both F; R₃ and R₄ are both methyl; and R′ isH.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ is F.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₁ and R₂ are both F.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ is F.

In another embodiment, this invention provides a compound of formulaIA-3, wherein R₁ and R₂ are both F.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is isoxazolyl orisothiazolyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is quinolyl orisoquinolyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is pyrimidyl orpurinyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is indolyl,isoindolyl, or benzimidazolyl.

In an embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is halo phenyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is dihalophenyl ordihalopyridyl.

In another embodiment, invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is mono- ordi-halothienyl, mono- or di-halofuryl, mono- or di-halobenzothienyl, ormono- or di-halobenzofuryl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is o-, m-, or p-xylylor o-, m-, or p-anisyl.

In another embodiment, this invention provides a compound of formula I,wherein R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, wherein Ar is m- orp-cyanophenyl or m- or p-cyanomethyl phenyl.

In another embodiment, this invention provides a compound of formula I,in which R₃ and R₄ are halogen, CF₃, or C₁-C₃ alkyl and R₅ is C₁-C₆alkyl, wherein the alkyl group is substituted with one or two groupsselected, independently, from OH, OMe, OEt, F, CF₃, Cl, or CN.

In another embodiment, this invention provides a compound of formula I,in which R₃ and R₄ are halogen, CF₃, OCF₃, C₁-C₃ alkyl, or OC₁-C₃ alkyl,and R₅ is (CH₂)_(w)C₃-C₆ cycloalkyl, wherein w is 1 or 2, wherein thecycloalkyl group is substituted with Me, OH, OMe, OEt, F, CF₃, Cl, orCN.

In an embodiment, this invention provides a compound of formula IA-1, inwhich R₃ and R₄ are halogen, CF₃, or C₁-C₃ alkyl, and R₅ is(CH₂)_(w)—C₅-C₆ cycloalkyl, optionally substituted, or (CH₂)_(w)—C₅-C₆heterocycloalkyl, optionally substituted.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is CH₂phenyl or CH₂CH₂-phenyl.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₁ is Ar, CH₂Ar or CH₂CH₂—Ar, wherein Ar is3,5-dichlorophenyl or 3,5-difluorophenyl.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl; R₃ and R₄ are H or C₁-C₆ alkyl,unsubstituted or substituted with one or two groups selected from OH,OMe; and R₆ is CN, CH₂CN, or halogen.

In another embodiment, this invention provides a compound of formulaIA-1, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar, wherein Ar is phenyl or pyridyl; and R₁ is F, CH₂F,CHF₂, CF₃, or CF₂CF₃.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, and R₁ is OC₁-C₆ alkyl or C(═O)C₁-C₆alkyl.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR6)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, and R₁ is C(═O)OC₁-C₆alkyl orOC(═O)C₁-C₆ alkyl.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, R₁ is C₂-C₆ alkenyl or C₂-C₆ alkynyl, qis 1, and X and Y are both O.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, Aris phenyl or pyridyl, and R₁ is SC₁-C₆ alkyl.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, R₃ and R₄ are H, Cl, methoxy, or C₁-C₃alkyl, and R₁ is C₁-C₆ alkyl.

In an embodiment, this invention provides a compound of formula IA-2,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl; R₃ and R₄ are H, Cl, methoxy, or C₁-C₂alkyl, unsubstituted or substituted with one or two groups selected fromOH, OMe; and R₁ is CN, CH₂CN, or halogen.

In another embodiment, this invention provides a compound of formulaIA-2, wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or(CHR₆)_(w)CH₂Ar, wherein Ar is phenyl or pyridyl; and R₁ is F, CH₂F,CHF₂, CF₃, or CF₂CF₃.

In an embodiment, this invention provides a compound of formula IA-1,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, and R₁ is OC₁-C₆ alkyl or C(═O)C₁-C₆alkyl.

In an embodiment, this invention provides a compound of formula IA-2,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, and R₁ is OC₁-C₆ alkyl orC(═O)C₁-C₆alkyl.

In an embodiment, this invention provides a compound of formula IA-3,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, and R₁ is OC₁-C₆ alkyl or C(═O)C₁-C₆alkyl.

In an embodiment, this invention provides a compound of formula IA-3,wherein R′ is phenyl or methoxy, R₂ is H, and R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, wherein Ar is phenyl or pyridyl,and R₁ is C(═O)OC₁-C₆alkyl or OC(═O)C₁-C₆alkyl.

In an embodiment, this invention provides a compound of formula IA-2,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, Aris phenyl or pyridyl, and R₁ is SC₁-C₆ alkyl.

In an embodiment, this invention provides a compound of formula IA-2,wherein R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar,wherein Ar is phenyl or pyridyl, R₃ and R₄ are H or C₁-C₃ alkyl, and R₁is C₁-C₆ alkyl.

In another embodiment, this invention provides a method of treating orpreventing a disease, disorder, or condition that is affected bymodulation of potassium ion channels in a patient comprisingadministration of a compound of formula I in an amount of up to about2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a disease, disorder, or condition that is affected bymodulation of potassium ion channels in a patient comprisingadministration of a compound of formula I in an amount of from about 10mg to about 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a disease, disorder, or condition that is affected bymodulation of potassium ion channels in a patient comprisingadministration of a compound of formula IA-1 in an amount of up to about2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula I in an amount of up to about 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula I in an amount of from about 10 mg per day toabout 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula I in an amount of from about 300 mg per day toabout 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula I in an amount of from about 300 mg per day toabout 1200 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula IA-1 in an amount of up to 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula IA-1 in an amount of from about 10 mg per day toabout 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula IA-1 in an amount of from about 300 mg per day toabout 2000 mg per day.

In another embodiment, this invention provides a method of treating orpreventing a seizure disorder in a patient comprising administration ofa compound of formula IA-1 in an amount of from about 300 mg per day toabout 1200 mg per day.

DETAILED DESCRIPTION OF INVENTION

As provided by this invention, compounds of formula IA are designed fororal or intravenous dosing of up to 2000 mg per day. Yet the highactivities of many of these compounds indicate that dosing of less than1200 mg per day—the current anticipated dosing level of retigabine inadults is possible. Thus, this invention comprises tablets, capsules,solutions, and suspensions of compounds of formula IA which areformulated for oral administration. Similarly, solutions and suspensionssuitable for oral pediatric administration, comprising, in addition tocompounds of formula IA, a syrup such as sorbitol or propylene glycol,among many other examples, are also contemplated. ally, solutions andsuspensions comprising, in addition to compounds of formula IA, a syrupsuch as sorbitol or propylene glycol, along with colorants andflavorings suitable for oral pediatric administration, are alsocontemplated. Additionally, both chewable and non-chewable tabletscomprising compounds of formula IA, along with pharmaceuticallyacceptable tabletting agents and other pharmaceutically acceptablecarriers and excipients, are also contemplated. As used herein, the termpharmaceutically acceptable carrier comprises such excipients, binders,lubricants, tabletting agents, disintegrants, preservatives,anti-oxidants, flavours and colourants as are typically used in the artof formulation of pharmaceuticals. Examples of such agents include—butare not limited to—starch, calcium carbonate, dibasic calcium phosphate,dicalcium phosphate, microcrystalline cellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose lactose, polyethylene glycols,polysorbates, glycols, safflower oil, sesame oil, soybean oil, andPovidone. Additionally, disintegrants such as sodium starch glycolate;lubricants such as magnesium stearate, stearic acid, and SiO₂; andsolubility enhancers such as cyclodextrins, among a great many otherexamples for each group, are contemplated. Such materials and themethods of using them are well known in the pharmaceutical art.Additional examples are provided in Kibbe, Handbook of PharmaceuticalExcipients, London, Pharmaceutical Press, 2000.

As used herein, the term “pharmaceutically acceptable acid salts” refersto acid addition salts formed from acids which provide non-toxic anions.The pharmaceutically acceptable anions include, but are not limited to,acetate, aspartate, benzoate, bicarbonate, carbonate, bisulfate,sulfate, chloride, bromide, benzene sulfonate, methyl sulfonate,phosphate, acid phosphate, lactate, maleate, malate, malonate, fumarate,lactate, tartrate, borate, camsylate, citrate, edisylate, esylate,formate, fumarate, gluceptate, glucuronate, gluconate oxalate,palmitate, pamoate, saccharate, stearate, succinate, tartrate, tosylateand trifluoroacetate salts, among a great many other examples.Hemi-salts, including but not limited to hemi-sulfate salts, arelikewise contemplated.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

As is well known, pharmaceutically acceptable salts of compounds offormula I may be prepared by reaction of a compound of formula I withthe desired acid; by removal of a protecting group from a suitableprecursor of the compound of formula I or by ring-opening a suitablecyclic precursor, for example, a lactone or lactam, using the desiredacid or base; and by conversion of one salt of the compound of formula Ito another by reaction with an appropriate acid or base or by passagethrough an appropriate ion-exchange column.

As used herein, the term “pharmaceutically acceptable solvate” refers todescribe a molecular complex comprising the compound of the inventionand a stoichiometric amount of one or more pharmaceutically acceptablesolvent molecules, including but not limited to water and ethanol. Thus,the term solvate includes a hydrate as one example and an ethanolate asanother example.

The compounds of the present invention may possess one or moreasymmetric carbons. Accordingly, any optical isomers as separated andany mixtures including racimic mixtures are embraced by the scope of thepresent invention. Resolution of racemic mixtures can be accomplished bymethods known to those skilled in the art.

The compounds of the present invention may also exist as geometricisomers and in different tautomeric forms. Those geometric isomers andtautomeric forms are included within the scope of the present invention.

As used herein, modulation of ion channels refers to activating the ionchannels, to affecting the kinetics of opening and closing of the ionchannels, or to causing any change in the channel open probability ofthe ion channels.

Preparation of Compounds

The Preparation of Compounds of Formula I is Outlined in Schemes I andII.

While in the above Scheme I nitrophenol is exemplified, a great manysubstituted nitrophenols are known and are therefore embraced by SchemeI. Thus, for example, compounds of Formula I wherein R₃ and R₄ are CF₃,OCF₃, OC₁-C₃ alkyl or C₁-C₃ alkyl or C₁-C₃ alkyl can be prepared fromthe appropriate substituted nitrophenol starting material. Likewise theexemplified flurobenzylchloride of Scheme I can be replaced by a numberof other substituted benzyl chloride. For example, if the compounds ofFormula I wherein R₁ and R₂ are independently selected from C₁-C₆ alkyl,C₃-C₆ cycloalkyl or OC₁-C₆ alkyl can be prepared from the appropriatesubstituted benzyl chloride starting material. It is to be understoodthat while the benzyl chloride of Scheme I is substituted by a single Rgroup, a second R group which would correspond to the R₁ and R₂ groupsof Formula I is included.

While Scheme I exemplifies the preparation of a substituted carbamicacid ethyl ester wherein the ethyl group would correspond to the R₅position of Formula I, it is to be understood that substitution of theappropriate reagent for the diethyl pyrocarbonate of Scheme I wouldyield the corresponding moiety which is defined by R₅.

1-nitro-4-(4-fluorobenzyloxy)-benzene

A mixture of 4-nitrophenol (1.39 g, 10 mmol), potassium carbonate (1.38g, 10 mmol) and 4-fluorobenzyl bromide (1.89 g, 10 mmol) in 20 ml ofanhydrous DMF was stirred at 100° C. for 2 days. After cooling to roomtemperature, the reaction mixture was poured into 200 ml of ice-waterwith stirring. The solid was filtered and washed with water and dried togive 2.37 g (96%) of 1-nitro-4-(4-fluorobenzyloxy)-benzene as yellowsolids.

The following compounds were synthesized by the same procedure:

-   1-Nitro-2-fluoro-4-(4-fluorobenzyloxy)-benzene, yellow solids, 96%-   1-Nitro-2-methyl-4-(4-fluorobenzyloxy)-benzene, yellow solids, 97%-   1-Nitro-2-trifluoromethyl-4-(4-fluorobenzyloxy)-benzene, yellow    solids, 95%-   1-Nitro-3-fluoro-4-(4-fluorobenzyloxy)-benzene, yellow solids, 91%-   1-Nitro-3-chloro-4-(4-fluorobenzyloxy)-benzene, yellow solids, 85%-   1-Nitro-3-methoxy-4-(4-fluorobenzyloxy)-benzene, yellow solids, 97%

4-(4-Fluoro-benzyloxy)-aniline

1-Nitro-4-(4-fluorobenzyloxy)-benzene (2.37 g) was dissolved in 200 mlof methanol and catalytic amount of Raney Ni was added. The mixture wasstirred at room temperature under atmospheric pressure in a hydrogenatmosphere for 3 hours. After filtering off Raney Ni over Celite andwashing with methanol, the obtained filtrate was concentrated underreduced pressure to give a solid product 4-(4-fluoro-benzyloxy)-aniline,which is pure enough for next step.

The following compounds were synthesized by the same procedure:

-   2-Fluoro-4-(4-Fluoro-benzyloxy)-aniline-   2-Trifluoromethyl-4-(4-Fluoro-benzyloxy)-aniline-   2-Methyl-4-(4-Fluoro-benzyloxy)-aniline-   3-Fluoro-4-(4-Fluoro-benzyloxy)-aniline-   3-Chloro-4-(4-Fluoro-benzyloxy)-aniline-   3-Methoxy-4-(4-Fluoro-benzyloxy)-aniline.

[4-(4-Fluoro-benzyloxy)-phenyl]carbamic acid ethyl ester

4-(4-Fluoro-benzyloxy)-aniline (0.22 g, 1 mmol) was dissolved in 8 ml ofanhydrous ethanol and diethyl pyrocarbonate (0.20 g, 1.2 mmol) was addeddropwise at room temperature. The resulting mixture was stirred at roomtemperature for 4 hours, then stored at −20° C. overnight. The crystalswas filtered and washed with cold ethanol to give pure product ascrystal solids (88 mg, 30%). The filtrate was concentrated to drynessunder reduced pressure and the residue was purified by silica gel columnto give another batch of pure products. ¹H NMR (DMSO-d₆, 300 MHz): δ9.38(brs, 1H, exchangeable with D₂O, NH), 7.46 (dd, J=5.7 and 8.1 Hz, 2H),7.32 (d, J=8.7 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H),5.00 (s, 2H), 4.07 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H). MS: 288(M−1).

The following compounds were synthesized by the same procedure:

[2-Methyl-4-(4-fluoro-benzyloxy)-phenyl]-carbamic acid ethyl ester

¹H NMR (DMSO-d₆, 300 MHz): δ 8.62 (brs, 1H, exchangeable with D₂O, NH),7.46 (dd, J=5.7 and 8.1 Hz, 2H), 7.19 (t, J=8.7 Hz, 2H), 7.12 (d, J=8.7Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 6.76 (dd, J=2.7 and 8.7 Hz, 1H), 5.02(s, 2H), 4.04 (q, J=7.2 Hz, 2H), 2.12 (s, 3H), 1.19 (t, J=7.2 Hz, 3H).MS: 302 (M−1).

[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]carbamic acid ethyl ester

¹H NMR (DMSO-d₆, 300MHz): δ 8.97 (brs, 1H, exchangeable with D₂0, NH),7.47 (dd, J=5.7 and 8.1 Hz, 2H), 7.37 (t, J=8.71 Hz, 1H), 7.20 (t, J=8:7Hz, 2H), 6.93 (dd, J=2.7 and 12.3 Hz, 1H), 6.78 (dd, J=2.7 and 8.7 Hz,1H), 5.05 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). MS:307 (M−1).

[2-Trifluoromethyl-4-(4-fluoro-benzyloxy)-phenyl]carbamic acid ethylester

¹H NMR (DMSO-d₆, 300 MHz): δ 8.83 (brs, 1H, exchangeable with D₂0, NH),7.50 (dd, J=5.7 and 8.1 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.21 (t, J=8.7Hz, 2H), 7.26 (dd, J=2.7 and 8.7 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 5.15(s, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H). MS: 356 (M−1).

[3-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-carbamic acid ethyl ester

¹H NMR (DMSO-d₆, 300 MHz): δ 9.61 (brs, 1H, exchangeable with D₂0, NH),7.46 (dd, J=5.7 and 8.1 Hz, 2H), 7.36 (dd, J=1.8 and 13.8 Hz, 1H), 7.20(t, J=8.7 Hz, 2H), 7.16 (d, J=9.0 Hz, 1H), 7.09 (dd, J=1.8 and 9.0 Hz,1H), 5.06 (s, 2H), 4.08 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). MS:306 (M−1).

[3-Chloro-4-(4-fluoro-benzyloxy)-phenyl]-carbamic acid ethyl ester

¹H NMR (DMSO-d₆, 300 MHz): δ 9.59 (brs, 1H, exchangeable with D₂0, NH),7.55 (d, J=1.8 Hz, 1H), 7.48 (dd, J=5.7 and 8.7 Hz, 2H), 7.29 (dd, J=1.8and 8.7 Hz, 1H), 7.21 (t, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 1H), 5.10(s, 2H), 4.08 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). MS: 322 (M−1).

[3-Methoxy-4-(4-fluoro-benzyloxy)-phenyl]carbamic acid ethyl ester

¹H NMR (DMSO-d₆, 300 MHz): δ 9.40 (brs, 1H, exchangeable with D₂0, NH),7.45 (dd, J=5.7 and 8.4 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 7.18 (m, 1H),6.89 (m, 2H), 4.96 (s, 2H), 4.08 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz,3H). MS: 318 (M−1).

While in the above scheme II 3,5-dimethylphenol is exemplified, a greatmany substituted phenols are known and are embraced by this scheme. Thusfor example, compounds of formula I wherein R₃ and R₄ are CF₃,OCF₃OC₁-C₃ alkyl or C₁-C₃ alkyl can be prepared from the appropriatesubstituted or disubstituted phenol starting material to arrive at thecorresponding nitrophenol. Likewise the exemplified (fluoro)-benzylchloride of the above scheme can be replaced by a number of othersubstituted benzyl chlorides. For example if compound of formula Iwherein R₁ and R₂ are independently selected C₁-C₃ alkyl, C₁-C₃cycloalkyl or OC₁-C₆ alkyl can be prepared from the appropriatesubstituted benzyl chloride starting material. It is to be understoodthat while the benzyl chloride of Scheme I is substituted by a single Rgroup, a second R group which would correspond to the R₁ and R₂ groupsof formula I is included.

In the above scheme II, R₁ of scheme II would correspond to R₅ offormula I and R would correspond to R₁ and R₂ of formula I.

3,5-Dimethyl-4-nitrophenol

[3,5-Dimethyl-4-nitrophenol was synthesized by the reference procedures(U.S. Pat. No. 4,564,640) J 750 ml of Concentrated hydrochloric acid wasadded to a solution of 3,5-dimethylphenol (80.6 g) in 750 ml of 95%ethanol. The mixture was cooled to 0° C. in an ice/methanol bath. Whilemaintaining the temperature of the reaction mixture below 5° C., asolution of NaNO2 (69.0 g) in 150 ml of water was added dropwise to thereaction mixture. The mixture was stirred at 0° C. for more than an hourand then poured into 9 liters of water. The aqueous mixture was filteredto give a yellow solid which was recrystallized from hot methanol andfiltered to give 71.45 g of 3,5-dimethyl-4-nitrosophenol as a yellowsolid. Mp. 180-181° C.

A mixture of 3,5-dimethyl-4-nitrosophenol (70.63 g) from above and(NH₄)₆Mo₇O₂₄.4H₂O) (2.83 g) in 770 ml of glacial acetic acid was warmedto 100° C. 30% H₂O₂ (84 ml) was added to the mixture in 10 ml portionsuntil an exothermic reaction was observed. The reaction mixture was thenstirred and the remainder of the H₂O₂ solution added in small portions.The reaction mixture was heated and stirred until a clear dark redsolution results. A yellow-orange solid precipitated from the solutionafter stirring for another 20-30 minutes. The reaction mixture wasstirred overnight and filtered to give a small amount of a yellow solidand a clear dark red filtrate. The red filtrate was concentrated invacuo and partitioned between water and ether. The aqueous layer waswashed with ether and the combined ether extracts washed with 10% sodiumcarbonate until the aqueous layer becomes basic. The ether extract wasdried over anhydrous sodium sulfate, filtered, concentrated and allowedto cool overnight. After cooling in an ice bath the mixture was filteredto give 49.5 g of 3,5-dimethyl-4-nitrophenol as a yellow-green solid.Mp. 106-108° C.

5-(4-Fluoro-benzyloxy)-2-nitro-meta-xylene

A mixture of 3,5-dimethyl-4-nitrophenol (0.97 g, 5.79 mmol),4-fluorobenzyl chloride (1.26 g, 8.69 mmol) and anhydrous potassiumcarbonate (1.24 g, 9.0 mmol) in 50 ml of acetone was stirred underreflux for 22 hours. TLC showed this reaction is complete. The reactionmixture was cooled to room temperature and filtered and washed withacetone. The filtrate was evaporated to dryness to give the crudeproduct, which was used for next step without further purification.

The following compounds were synthesized by the same procedure:

-   5-(4-Chloro-benzyloxy)-2-nitro-meta-xylene-   5-(4-Bromo-benzyloxy)-2-nitro-meta-xylene-   5-(4-Methyl-benzyloxy)-2-nitro-meta-xylene-   5-(4-Trifluoromethyl-benzyloxy)-2-nitro-meta-xylene-   5-(2-Trifluoromethyl-benzyloxy)-2-nitro-meta-xylene-   5-(3-Trifluoromethyl-benzyloxy)-2-nitro-meta-xylene-   5-(3-Chloro-benzyloxy)-2-nitro-meta-xylene-   5-(3-Fluoro-benzyloxy)-2-nitro-meta-xylene-   5-(2,4-Difluoro-benzyloxy)-2-nitro-meta-xylene-   5-(3,4-Difluoro-benzyloxy)-2-nitro-meta-xylene

4-(4-Fluoro-benzyloxy)-2,6-dimethylaniline

1-Nitro-4-(4-fluorobenzyloxy)-benzene (0.5 g) was dissolved in 60 ml ofmethanol and catalytic amount of Raney Ni was added. The mixture wasstirred at room temperature under atmospheric pressure in a hydrogenatmosphere for 3 hours. After filtering off Raney Ni over Celite andwashing with methanol, the obtained filtrate was concentrated underreduced pressure to give a solid product4-(4-fluoro-benzyloxy)-2,6-dimethylaniline, which is pure enough fornext step.

The following compounds were synthesized by the same procedure:

-   4-(4-Chloro-benzyloxy)-2,6-dimethylaniline-   4-(4-Bromo-benzyloxy)-2,6-dimethylaniline-   4-(4-Methyl-benzyloxy)-2,6-dimethylaniline-   4-(3,4-Difluoro-benzyloxy)-2,6-dimethylaniline-   4-(2,4-Difluoro-benzyloxy)-2,6-dimethylaniline-   4-(4-Trifluoromethyl-benzyloxy)-2,6-dimethylaniline-   4-(3-Trifluoromethyl-benzyloxy)-2,6-dimethylaniline-   4-(2-Trifluoromethyl-benzyloxy)-2,6-dimethylaniline-   4-(3-Fluoro-benzyloxy)-2,6-dimethylaniline-   4-(3-Chloro-benzyloxy)-2,6-dimethylaniline

N-[4-(4-Fluoro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

To a solution of 4-(4-fluoro-benzyloxy)-2,6-dimethylaniline (0.20 g,0.82 mmol) from above and triethylamine (125 mg, 1.24 mmol) in anhydrousmethylene chloride (20 ml) was added dropwise tert-butylacetyl chloride(135 mg, 1 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture, andthe mixture was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ISCO, hexane/EtOAc,0-40%, 40 min) and recrystallized from hexane/EtOAc (5:1) to give 230 mg(82%) of the white solids. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.92 (brs, 1H,exchangeable with D₂0, NH), 7.46 (dd, J=4.7 and 6.4 Hz, 2H), 7.19 (t,J=7.0 Hz, 2H), 6.70 (s, 2H), 5.02 (s, 2H), 2.16 (s, 2H), 2.08 (s, 6H),1.03 (s, 9H). MS: 344 (M+1).

The following compounds were synthesized by the same procedure:

N-[4-(4-Chloro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.94 (brs, 1H, exchangeable with D₂0, NH),7.46 (s, 4H), 6.72 (s, 2H), 5.07 (s, 2H), 2.18 (s, 2H), 2.10 (s, 6H),1.05 (s, 9H). MS: 360 (M+1).

N-[4-(4-Bromo-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.94 (brs, 1H, exchangeable with D₂O, NH),7.59 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.71 (s, 2H), 5.05 (s,2H), 2.18 (s, 2H), 2.10 (s, 6H), 1.05 (s, 9H). MS: 404 (M+1).

N-[4-(4-Methyl-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.94 (brs, 1H, exchangeable with D₂0, NH),7.30 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.70 (s, 2H), 5.01 (s,2H), 2.31 (s, 3H), 2.18 (s, 2H), 2.09 (s, 6H), 1.05 (s, 9H). MS: 340(M+1).

N-[4-(4-Trifluoromethyl-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.95 (brs, 1H, exchangeable with D₂0, NH),7.76 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 6.74 (s, 2H), 5.19 (s,2H), 2.18 (s, 2H), 2.10 (s, 6H), 1.05 (s, 9H). MS: 394 (M+1).

N-[4-(2-Trifluoromethyl-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.96 (brs, 1H, exchangeable with D₂0, NH),7.80 (d, J=8.0 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H),7.59 (t, J=8.0 Hz, 1H), 6.72 (s, 2H), 5.19 (s, 2H), 2.19 (s, 2H), 2.11(s, 6H), 1.05 (s, 9H). MS: 394 (M+1).

N-[4-(3-Trifluoromethyl-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.96 (brs, 1H, exchangeable with D₂0, NH),7.80 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.64 (t,J=8.0 Hz, 1H), 6.75 (s, 2H), 5.18 (s, 2H), 2.19 (s, 2H), 2.11 (s, 6H),1.05 (s, 9H). MS: 394 (M+1).

N-[4-(3-Chloro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.94 (brs, 1H, exchangeable with D₂0, NH),7.50 (s, 1H), 7.41 (m, 3H), 6.73 (s, 2H), 5.09 (s, 2H), 2.18 (s, 2H),2.10 (s, 6H), 1.05 (s, 9H). MS: 360 (M+1).

N-[4-(3-Fluoro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.94 (brs, 1H, exchangeable with D₂0, NH),7.50 (s, 1H), 7.41 (m, 3H), 6.73 (s; 2H), 5.09 (s, 2H), 2.18 (s, 2H),2.10 (s, 6H), 1.05 (s, 9H). MS: 360 (M+1).

N-[4-(2,4-Difluoro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.96 (brs, 1H, exchangeable with D₂0, NH),7.61 (dd, J=8.3 and 15.3 Hz, 1H), 7.30 (dt, J=2.2 and 10.1 Hz, 1H), 7.13(dt, J=2.2 and 8.3 Hz, 1H), 6.74 (s, 2H), 5.06 (s, 2H), 2.19 (s, 2H),2.11 (s, 6H), 1.05 (s, 9H). MS: 362 (M+1).

N-[4-(3,4-Difluoro-benzyloxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.93 (brs, 1H, exchangeable with D₂0, NH),7.49 (t, J=7.7 Hz, 1H), 7.43 (dd, J=6.9 and 15.2 Hz, 1H), 7.28 (m, 1H),6.70 (s, 2H), 5.03 (s, 2H), 2.16 (s, 2H), 2.08 (s, 6H), 1.03 (s, 9H).MS: 362 (M+1).

3-Cyclopentyl-N-[4-(3,4-difluoro-benzyloxy)-2,6-dimethyl-phenyl]-propionamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.99 (brs, 1H, exchangeable with D₂0, NH),7.48 (t, J=7.7 Hz, 1H), 7.42 (dd, J=6.9 and 15.2 Hz, 1H), 7.28 (m, 1H),6.70 (s, 2H), 5.03 (s, 2H), 2.27 (t, J=6.0 Hz, 2H), 2.06 (s, 6H), 1.75(m, 3H), 1.60 (m, 4H), 1.47 (m, 2H), 1.10 (m, 2H). MS: 388 (M+1).

3-Cyclopentyl-N-[4-(4-fluoro-benzyloxy)-2,6-dimethyl-phenyl]-propionamide

¹H NMR (DMSO-d6, 400 MHz): δ 8.98 (brs, 1H, exchangeable with D20, NH),7.46 (dd, J=4.7 and 6.5 Hz, 2H), 7.20 (t, J=7.0 Hz, 1H), 6.69 (s, 2H),5.02 (s, 2H), 2.28 (t, J=6.0 Hz, 2H), 2.11 (s, 6H), 1.76 (m, 3H), 1.60(m, 4H), 1.47 (m, 2H), 1.10 (m, 2H). MS: 370 (M+1).

Biological Results

Compounds of this invention formula were evaluated for activity towardpotassium channels in a cell-based Rb⁺ efflux assay. This cellularbioassay is believed to faithfully represent the M current channelactivities identified with KCNQ2/3 heteromultimers. The most activecompounds of this invention have EC₅₀s in the single-digit nM range.Additionally, antiseizure activity in vivo was evaluated in a mousemaximal electroshock seizure (MES) model, and neurotoxicities weredetermined from a rotorod neurocognitive motor impairment model.

Methods:

Rubidium Efflux Test

PC-12 cells were grown at 37° C. and 5% CO₂ in DMEM/F12 Medium(Dulbecco's Modified Eagle Medium with Nutrient Mix F-12, available fromInvitrogen of Carlsbad, Calif.), supplemented with 10% horse serum, 5%fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, and 100 U/mlstreptomycin. They were plated in poly-D-lysine-coated 96-well cellculture microplates at a density of 40,000 cells/well and differentiatedwith 100 ng/ml NGF-7s for 2-5 days. For the assay, the medium wasaspirated, and the cells were washed once with 0.2 ml in wash buffer (25mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgCl₂; 0.8 mM NaH₂PO₄, 2 mM CaCl₂).The cells were then loaded with 0.2 ml Rh⁺ loading buffer (wash bufferplus 5.4 mM RbCl₂, 5 mM glucose) and incubated at 37° C. for 2 h.Attached cells were quickly washed three times with buffer (same as Rb⁺loading buffer, but containing 5.4 mM KCl instead of RbCl) to removeextracellular Rb⁺. Immediately following the wash, 0.2 ml ofdepolarization buffer (wash buffer plus 15 mM KCl) with or withoutcompounds was added to the cells to activate efflux of potassium ionchannels. After incubation for 10 min at room temperature, thesupernatant was carefully removed and collected. Cells were lysed by theaddition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1%Triton X-100) and the cell lysates were also collected. If collectedsamples were not immediately analyzed for Rb⁺ contents by atomicabsorption spectroscopy (see below), they were stored at 4° C. withoutany negative effects on subsequent Rb⁺ analysis.

The concentrations of Rb⁺ in the supernatants (Rb⁺ _(Sup)) and the celllysates (Rb⁺ _(Lys)) were quantified using an ICR8000 flame atomicabsorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) underconditions defined by the manufacturer. Samples 0.05 ml in volume wereprocessed automatically from microtiter plates by dilution with an equalvolume of Rb⁺ sample analysis buffer and injection into an air-acetyleneflame. The amount of Rb⁺ in the sample was measured by absorption at 780nm using a hollow cathode lamp as light source and a PMT detector. Acalibration curve covering the range 0-5 mg/L Rb⁺ in sample analysisbuffer was generated with each set of plates. The percent Rb⁺ efflux (F)was defined byF=[Rb⁺ _(Sup)/(Rb⁺ _(Sup)+Rb⁺ _(Lys))]×100%.wherein the F_(c) is the efflux in the presence of compound indepolarization buffer, F_(b) is the efflux in basal buffer, and F_(s) isthe efflux in depolarization buffer, and F_(c) is the efflux in thepresence of compound in depolarization buffer. The efflux (F) andcompound concentration relationship was plotted to calculate an EC₅₀value, a compound's concentration for 50% of maximal RV efflux. Theresults are shown below in Table 1.Maximal Electroshock Seizure (MES) and Acute Toxicity TestsMES Test

The MES testing protocol is based on procedures established at theNational Institute of Neurological Disorders and Stroke in conjunctionwith the Anticonvulsant Screening Program (ASP) at the University ofUtah (White, H. S., Woodhead, J. H., Wilcox, K. S., Stables, J. P.,Kupferberg, H. J and Wolf, H. H. 2002. “General Principles: Discoveryand Preclinical Development of Antiepileptic Drugs,” in AntiepilepticDrugs, 5^(th) Edition, R. H. Levy, ed.; R. H. Mattson, B. S. Meldrum,and E. Perucca: Philadelphia, Lippincott Williams & Wilkins.), The goalof the test rapid identification and characterization of the in vivoanticonvulsant activity of any compounds that have been shown active inPC-12 cellular based RV efflux assay.

Adult male CF-1 albino mice (18-25 g, Charles River Laboratories) areexclusively used for in-house MES screen of compounds. MaleSprague-Dawley albino rats (100-125 g, Charles River Laboratories) arealso used to test anticonvulsant compounds. Variability of test outcomesis reduced by using animals of the same sex, age, and weight. Animalsare permitted to rest and recover from transit for at least 48 hr priorto experimentation. Animals are used for AED testing only once. In someinstances, the animals may be anesthetized prior to blood collectionand/or whole brain extraction for pharmacokinetic assay. All animals aremaintained and handled as outlined in standard animal care guidelines.

In the experiments, testing compounds are prepared as suspensions in0.5% methyl cellulose (Sigma, Cat #M0512, Viscosity 4000 cP at 20° C.)in water, regardless of solubility. Dry powder compounds are initiallyground with a glass rod in a test tube in several drops of methylcellulose to create a paste and to break down any large chunks. Afterseveral minutes of grinding, the volume of the suspension is increasedto the final concentration desired. The suspension is then sonicatedusing a Branson sonicator model 3510 in a water bath at room temperaturefor 15 minutes. Compound suspensions are further vortexed prior toanimal dosing. In some of the cases, DMSO is used to initiallysolubilize compounds in small volumes and then this solution is added tothe 0.5% methyl cellulose solution, in order to create more even andless aggregated compound suspensions. The final concentration of DMSO is3.75%, an amount with no apparent toxicity or neuroprotective effects inour usual rotarod and MES tests. Methyl cellulose/DMSO compoundsuspensions are identically prepared for intraperitoneally (i.p.) tomice or orally (p.o.) to rat dosing.

Initially the animals are weighed with an electronic scale and thenmarked. Data recording sheets are generated for each compoundassessment. Mice or rats are dosed with the compound suspension at 0.01mL/g of body weight. The typical injection volume range is between180-250 μl for mice. Compounds are dosed by i.p. to mice using a 25 or22 gauge needle, depending on the viscosity of the suspension. Rats arep.o. dosed using a flexible feeding tube, typically starting at acompound dose of 5 mg/kg.

A Rodent Electroconvulsive Stimulator (Model 200, Hamit-Darvin-Freesh,Snow Canyon Clinic, Ivins, Utah) is used for MES testing. A 60-Hzalternating current (50 mA for mice; 150 mA for rats) is delivered for0.2 seconds through corneal electrodes to the mice. A drop of 0.5%tetracaine (Sigma, Cat. #T-7508) solution is placed on the eye prior tocurrent delivery. The electrodes are subsequently placed gently onto theeyes of the animal and the electrical shock is initiated by triggeringthrough a foot-pedal activator. The animals are restrained by hand andgently released as the shock is delivered and the seizure commences.Animals are monitored for hind limb tonic extension as the end point forthis test. Current delivery is recorded as a measure of overallseizure-induction potential. Electrical current delivery can vary fromapproximately 30-55 mA (mice) or 90-160 mA (rats) depending on impedancein the animal and quality of the current delivery (i.e., correctplacement of the electrodes on the cornea). Seizures will besuccessfully induced in control animals throughout this current range.Tonic extension is considered abolished if the hind limbs fail to becomefully extended at 180° with the plane of the body. Lack of tonicextension suggests that the test compound has prevented the spread ofseizure discharge through neural tissue. Although unnecessary in mice,the rats are pre-screened for seizure induction potential using the MES24hr prior to compound dosing and the subsequent MES test. A successrate of 92-100% has been determined for the rat seizure inductionpotential. Rats that fail to develop tonic/clonic seizures during thepre-screening are not used for drug testing.

For compound testing, time-to-peak effect studies are initiallyperformed using 0.5, 1, 2, 4, 8 and 24 hr time points, typically using asingle 5 or 25 mg/kg dose. The determined time-to-peak effect is usedfor further titration of a compound's potency (ED₅₀, the dose of a drugthat protects 50% of animals from electrical induced seizure) in bothmouse and rat models. For titrations, 8 animals are used perconcentration and dose (normal 5 concentrations) is varied until a fulldose response curve can be obtained. Probit analysis (ASP method) ornon-linear regression analysis on Graph Pad (constraining the lowerdose/effect value) is used to calculate an ED₅₀ value for the testcompound.

Rotarod Test

Prior to MES testing, compound dosed mice are scrutinized for abnormalneurologic status as defined by motor impairment on a slowly turning (6rpm) rotarod apparatus (Model 755, Series 8, IITC Life Sciences,Woodland Hills, Calif.). The inability of a mouse to maintain itsbalance on the rotarod over a period of one minute (three falls=failure)signifies motor impairment and hence acute toxicity. These measurementsare done at the same time points as the MES assay. Untreated normal miceare able to maintain balance on the rotarod for at least one minutewithout falling. Median toxicity of a compound (TD₅₀, the dose of a drugthat results in motor impairment in 50% of animals) is determined.

Open Field Test

Before the MES test, compound treated rats are visually observed foracute toxicity signs for approximately one minute in the open fieldtest. Here, rats are gently placed into a plexiglass enclosure and aremonitored for behavior consistent with toxicity including ataxia,trembling, hypoactivity (including failure to seek the walls),hypersensitivity, lack of exploratory behavior and lack of avoidance ofthe open area. Typically if the rats exhibits two or more of theseabnormal behaviors they are scored as toxic.

TABLE 1 ACTIVITIES OF EXEMPLARY COMPOUNDS ACTIVITY COMPOUND EC₅₀

D

D

D

D

B

C

B

C

C

C

D

C

C

C

C

C

C Legend: A: EC₅₀ ≦ 1 nM; B: = 1 nM < EC₅₀ ≦ 10 nM; C: 10 nM < EC₅₀ ≦ 50nM; D: 50 nM < EC₅₀ ≦ 500 nMStudies of KCNQ2/3 Opening Activity and KCNQ Subtype Selectivity UsingElectrophysiological Patch Clamp in Xenopus OocytesExpression in Xenopus Laevis Oocytes

Female Xenopus laevis extracted ovaries can be purchased from eNASCO(LM00935MX, eNASCO Fort Atkinson, Wis.). Following manual dissection ofthe oocytes into smaller groups, the oocytes are defolliculated byenzymatic treatment with collagenase type 2 (LS004177, Worthington,Lakewood, N.J.) for 1½ hour in the presence of calcium-free Culture Bathsolution (88 mM NaCl, 1 mM KCl, 0.82 mM MgSO₄, 2.4 mM NaHCO₃, and 5 mMHEPES, pH 7.5). Oocytes are then kept in supplemented Culture Bathsolution (88 mM NaCl, 1 mM KCl, 0.82 mM MgSO₄, 0.9 mM CaCl₂, 2.4 mMNaHCO₃, 1 mM sodium pyruvate, 0.05 mg/ml Geneticin, 100 U/ml penicillin,0.1 mg/ml streptomycin and 5 mM HEPES, pH 7.5) at 19° C. for 24 hoursbefore injection of cRNA. Approximately 50 nl cRNA (about 50 ng) isinjected for KCNQ1, KCNQ4, and KCNQ5 using a Nanoject microinjector(Drummond, Broomall, Pa., USA). For co-expression of KCNQ2 and KCNQ3 andof KCNQ1 and KCNE1, cRNA's are mixed in equal molar ratios beforeinjection of approximately 50 nl. The mixtures contain about 10+10 ngand 12.5+2.5 ng cRNA, respectively. The smaller amounts are neededbecause larger currents arise when KCNQ2/KCNQ3 and KCNQ1/KCNE1 areco-expressed. Oocytes are kept in Culture Barth solution at 19° C. whichis changed daily and currents are recorded after 3 to 5 days.

Electrophysiology

KCNQ channel currents expressed in Xenopus laevis oocytes are recordedusing a two-electrode voltage-clamp. The recordings are made at roomtemperature in recording solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 1.8mM CaCl₂, and 5 mM HEPES, pH 7.5) using a two-electrode voltage-clampamplifier (OC-725C, Warner Instrument, Hamden, Conn., USA). The oocytesare placed in custom built perfusion chambers connected to a continuousflow system and impaled with a current electrode and a voltage-clampelectrode pulled from borosilicate glass on a Flaming/Brown MicropipettePuller (Sutter Instruments Co., Novato, Calif., USA). Recordingelectrodes are filled with 3 M KCl and had a resistance of 0.5 to 2.5MΩ.

Compounds

All compounds are dissolved in DMSO to obtain concentrated stocksolutions. On the day of electrophysiological experiments the stocksolutions are thawed and diluted in recording solution to their finalconcentrations. The final DMSO concentration never exceeds 0.1%.Compound delivery is performed using a custom built multi-barrelapparatus connected to the flow system.

Calculations

Data are acquired by means of an Axograph X software (AxographScientific, Sydney, AU) and analyzed using Graph Pad Prism (GraphPadSoftware Inc., Calif., USA).

Concentration—response curves are constructed by plotting the increasein steady-state current expressed in percentages as a function of drugconcentration. During the course of the experiment, while variousconcentrations of the drug are being dosed, the resting voltage is heldat −90 mV and pulsed to −60 mV, −40 mV, and −50 mV for 5 s forKCNQ2/KCNQ3, KCNQ4 and KCNQ5 channels respectively. The plot was thenfitted to a Hill function:Response=R2+(R1−R2)/[1+(C/EC ₅₀)^nH]wherein R1 is the initial response, R2 is the maximum response, C is thedrug concentration and nH is the slope (Hill coefficient) of the curve.

The efficacy of compounds of this invention in comparison withRetigabine (as a positive control) are determined by recording thesteady current using the above voltage protocol for the channels in thepresence of the EC₇₅ of the drugs. After steady channel current isrecorded in the presence of Retigabine at its EC75, recorded oocyte iswashed with the recording solution until its steady current returned toits normal level without the presence of any drugs. Then the channelsteady current is recorded in the presence of the test compound at itsEC₇₅. The percent efficacy is then expressed as:% efficacy=(C2/C1)×100%wherein C2 is the recorded steady current in the presence of follow-oncompound at its EC₇₅ and C1 is the recorded steady current in thepresence of Retigabine at its EC₇₅.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above methods and productswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A method of treating a seizure disordercomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound selected from

or a salt or ester thereof.